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Mechanism(s) Underlying Cardiovascular Effects of ARB/NEP Inhibition - Aim 2

Primary Purpose

Heart Failure NYHA Class I, Heart Failure NYHA Class II, Heart Failure NYHA Class III

Status
Withdrawn
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Valsartan 80 mg bid
Enalapril 10 mg bid
Sacubitril-Valsartan 200 mg bid
Icatibant
Placebo
Sponsored by
Vanderbilt University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Heart Failure NYHA Class I

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Stable patients with a reduced EF

    1. EF less than or equal to 40% (confirmed by echocardiogram within the last six months), and
    2. history of symptoms of New York Heart Association class I, II or III HF
    3. stable clinical symptoms including no hospitalizations for the last six months
    4. treatment with a stable dose of an ACEi or ARB and with a beta blocker (unless contraindicated or not tolerated) for at least four weeks
    5. treatment with a stable dose of an MR antagonist for at least four weeks unless not possible due to renal function or serum potassium.
  2. For female subjects, the following conditions must be met:

    1. postmenopausal status for at least one year, or
    2. status post-surgical sterilization

Exclusion Criteria:

  1. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEi, ARBs, or NEPi, as well as known or suspected contraindications to the study drugs
  2. History of angioedema
  3. History of pancreatitis or known pancreatic lesions
  4. History of decompensated HF within the last six months (exacerbation of chronic HF manifested by signs and symptoms that required intravenous therapy or hospitalization)
  5. History of heart transplant or on a transplant list or with left ventricular assistance device
  6. Symptomatic hypotension and/or a SBP<100 mmHg at screening or <90 mmHg during the study
  7. Serum potassium >5.2 mmol/L at screening or >5.4 mmol/L during the study
  8. Acute coronary syndrome, cardiac, carotid, or other major cardiovascular surgery, percutaneous coronary intervention, or carotid angioplasty within six months prior to screening
  9. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within six months of screening
  10. History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack within six months
  11. History of ventricular arrhythmia with syncopal episodes
  12. Symptomatic bradycardia or second- or third-degree atrioventricular block without a pacemaker
  13. Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to LV dilatation
  14. Presence of other hemodynamically significant obstructive lesions of the left ventricular outflow tract, including aortic and subaortic stenosis
  15. Type 1 diabetes
  16. Poorly controlled type 2 diabetes mellitus (T2DM), defined as a HgbA1c >9%
  17. Hematocrit <35%
  18. Impaired renal function (eGFR of <30mL/min/1.73 m2) as determined by the four-variable Modification of Diet in Renal Disease (MDRD) equation, where serum creatinine (Scr) is expressed in mg/dL and age in years:

    eGFR (mL/min/1.73m2)=175 • Scr-1.154 • age-0.203 • (1.212 if Black) • (0.742 if female)

  19. Use of hormone-replacement therapy
  20. Breast feeding and pregnancy
  21. History or presence of immunological or hematological disorders
  22. History of malignancy other than non-melanoma skin cancer
  23. Diagnosis of asthma requiring use of inhaled beta agonist more than once a week
  24. Clinically significant gastrointestinal impairment that could interfere with drug absorption
  25. Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) >3.0 x upper limit of normal range]
  26. Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult, such as arthritis treated with non-steroidal anti-inflammatory drugs
  27. Treatment with chronic systemic glucocorticoid therapy within the last year
  28. Treatment with lithium salts
  29. History of alcohol or drug abuse
  30. Treatment with any investigational drug in the one month preceding the study
  31. Mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study
  32. Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Sites / Locations

  • Vanderbilt University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm 11

Arm 12

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

S/V+Pla, S/V+I, Enal+Pla, Enal+I

S/V+Pla, Enal+I, S/V+I, Enal+Pla

S/V+Pla, Enal+Pla, Enal+I, S/V+I

S/V+I, S/V+Pla, Enal+I, Enal+P

S/V+I, Enal+Pla, S/V+Pla, Enal+I

S/V+I, Enal+I, Enal+Pla, S/V+Pla

Enal+Pla, S/V+Pla, S/V+I, Enal+I

Enal+Pla, S/V+I, Enal+I, S/V+Pla

Enal+Pla, Enal+I, S/V+Pla, S/V+I

Enal+I, S/V+Pla, Enal+Pla, S/V+I

Enal+I, S/V+I, S/V+Pla, Enal+Pla

Enal+I, Enal+Pla, S/V+I, S/V+Pla

Arm Description

Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

Outcomes

Primary Outcome Measures

change in systolic blood pressure
change in plasma cGMP

Secondary Outcome Measures

heart rate
renal plasma flow
glomerular filtration rate
change in diastolic blood pressure
fractional excretion of sodium
urine albumin-to-creatinine ratio
brain natriuretic peptide (BNP) to N-terminal pro-BNP ratio
plasminogen activator inhibitor-1
tissue plasminogen activator
aldosterone
urine cGMP

Full Information

First Posted
December 22, 2016
Last Updated
January 9, 2018
Sponsor
Vanderbilt University Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT03005184
Brief Title
Mechanism(s) Underlying Cardiovascular Effects of ARB/NEP Inhibition - Aim 2
Official Title
Mechanism(s) Underlying Cardiovascular Effects of ARB/NEP Inhibition - Aim 2
Study Type
Interventional

2. Study Status

Record Verification Date
January 2018
Overall Recruitment Status
Withdrawn
Why Stopped
Study is being redesigned and submitted as a new study.
Study Start Date
September 2017 (Anticipated)
Primary Completion Date
January 2020 (Anticipated)
Study Completion Date
January 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study tests the hypothesis that endogenous bradykinin contributes to effects of a combined angiotensin receptor blocker/neprilysin inhibitor (LCZ696 or Entresto)
Detailed Description
Patients with heart failure (HF) with reduced ejection fraction who qualify for the study will undergo a three-week run-in period in which any prior angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker they were taking will be discontinued and they will be given valsartan 80 mg bid in a single-blind fashion. After the run-in, subjects will undergo four study periods in random order. During two study periods they will receive enalapril 10 mg bid and during two they will receive sacubitril/valsartan (LCZ696) 200 mg bid for seven days. On the seventh day or each period, subjects will complete a study day in which they are randomized to receive either the bradykinin B2 receptor blocker icatibant or placebo intravenously. Each study period will be separated by a three-week washout during which subjects receive valsartan 80 mg bid.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure NYHA Class I, Heart Failure NYHA Class II, Heart Failure NYHA Class III

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
S/V+Pla, S/V+I, Enal+Pla, Enal+I
Arm Type
Experimental
Arm Description
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
Arm Title
S/V+Pla, Enal+I, S/V+I, Enal+Pla
Arm Type
Experimental
Arm Description
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
Arm Title
S/V+Pla, Enal+Pla, Enal+I, S/V+I
Arm Type
Experimental
Arm Description
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
Arm Title
S/V+I, S/V+Pla, Enal+I, Enal+P
Arm Type
Experimental
Arm Description
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
Arm Title
S/V+I, Enal+Pla, S/V+Pla, Enal+I
Arm Type
Experimental
Arm Description
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
Arm Title
S/V+I, Enal+I, Enal+Pla, S/V+Pla
Arm Type
Experimental
Arm Description
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
Arm Title
Enal+Pla, S/V+Pla, S/V+I, Enal+I
Arm Type
Experimental
Arm Description
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
Arm Title
Enal+Pla, S/V+I, Enal+I, S/V+Pla
Arm Type
Experimental
Arm Description
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
Arm Title
Enal+Pla, Enal+I, S/V+Pla, S/V+I
Arm Type
Experimental
Arm Description
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
Arm Title
Enal+I, S/V+Pla, Enal+Pla, S/V+I
Arm Type
Experimental
Arm Description
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
Arm Title
Enal+I, S/V+I, S/V+Pla, Enal+Pla
Arm Type
Experimental
Arm Description
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
Arm Title
Enal+I, Enal+Pla, S/V+I, S/V+Pla
Arm Type
Experimental
Arm Description
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
Intervention Type
Drug
Intervention Name(s)
Valsartan 80 mg bid
Intervention Description
oral medication during run-in and washout period
Intervention Type
Drug
Intervention Name(s)
Enalapril 10 mg bid
Intervention Description
oral medication
Intervention Type
Drug
Intervention Name(s)
Sacubitril-Valsartan 200 mg bid
Intervention Description
oral medication
Intervention Type
Drug
Intervention Name(s)
Icatibant
Intervention Description
intravenous medication
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
intravenous medication
Primary Outcome Measure Information:
Title
change in systolic blood pressure
Time Frame
7-hour period after 7-day intervention
Title
change in plasma cGMP
Time Frame
7-hour period after 7-day intervention
Secondary Outcome Measure Information:
Title
heart rate
Time Frame
7-hour period after 7-day intervention
Title
renal plasma flow
Time Frame
7-hour period after 7-day intervention
Title
glomerular filtration rate
Time Frame
7-hour period after 7-day intervention
Title
change in diastolic blood pressure
Time Frame
7-hour period after 7-day intervention
Title
fractional excretion of sodium
Time Frame
7-hour period after 7-day intervention
Title
urine albumin-to-creatinine ratio
Time Frame
7-hour period after 7-day intervention
Title
brain natriuretic peptide (BNP) to N-terminal pro-BNP ratio
Time Frame
7-hour period after 7-day intervention
Title
plasminogen activator inhibitor-1
Time Frame
7-hour period after 7-day intervention
Title
tissue plasminogen activator
Time Frame
7-hour period after 7-day intervention
Title
aldosterone
Time Frame
7-hour period after 7-day intervention
Title
urine cGMP
Time Frame
7-hour period after 7-day intervention

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Stable patients with a reduced EF EF less than or equal to 40% (confirmed by echocardiogram within the last six months), and history of symptoms of New York Heart Association class I, II or III HF stable clinical symptoms including no hospitalizations for the last six months treatment with a stable dose of an ACEi or ARB and with a beta blocker (unless contraindicated or not tolerated) for at least four weeks treatment with a stable dose of an MR antagonist for at least four weeks unless not possible due to renal function or serum potassium. For female subjects, the following conditions must be met: postmenopausal status for at least one year, or status post-surgical sterilization Exclusion Criteria: History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEi, ARBs, or NEPi, as well as known or suspected contraindications to the study drugs History of angioedema History of pancreatitis or known pancreatic lesions History of decompensated HF within the last six months (exacerbation of chronic HF manifested by signs and symptoms that required intravenous therapy or hospitalization) History of heart transplant or on a transplant list or with left ventricular assistance device Symptomatic hypotension and/or a SBP<100 mmHg at screening or <90 mmHg during the study Serum potassium >5.2 mmol/L at screening or >5.4 mmol/L during the study Acute coronary syndrome, cardiac, carotid, or other major cardiovascular surgery, percutaneous coronary intervention, or carotid angioplasty within six months prior to screening Coronary or carotid artery disease likely to require surgical or percutaneous intervention within six months of screening History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack within six months History of ventricular arrhythmia with syncopal episodes Symptomatic bradycardia or second- or third-degree atrioventricular block without a pacemaker Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to LV dilatation Presence of other hemodynamically significant obstructive lesions of the left ventricular outflow tract, including aortic and subaortic stenosis Type 1 diabetes Poorly controlled type 2 diabetes mellitus (T2DM), defined as a HgbA1c >9% Hematocrit <35% Impaired renal function (eGFR of <30mL/min/1.73 m2) as determined by the four-variable Modification of Diet in Renal Disease (MDRD) equation, where serum creatinine (Scr) is expressed in mg/dL and age in years: eGFR (mL/min/1.73m2)=175 • Scr-1.154 • age-0.203 • (1.212 if Black) • (0.742 if female) Use of hormone-replacement therapy Breast feeding and pregnancy History or presence of immunological or hematological disorders History of malignancy other than non-melanoma skin cancer Diagnosis of asthma requiring use of inhaled beta agonist more than once a week Clinically significant gastrointestinal impairment that could interfere with drug absorption Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) >3.0 x upper limit of normal range] Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult, such as arthritis treated with non-steroidal anti-inflammatory drugs Treatment with chronic systemic glucocorticoid therapy within the last year Treatment with lithium salts History of alcohol or drug abuse Treatment with any investigational drug in the one month preceding the study Mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study
Facility Information:
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Mechanism(s) Underlying Cardiovascular Effects of ARB/NEP Inhibition - Aim 2

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